Fake antigens and FAR/anaphylaxis
It is unclear what the clinical benefit of anaphylaxis may be. Perhaps
there is none, and systematic MC-degranulation is not a valuable option
in immune defense as it should not happen. If it occurs, it may be by
mistake, as the immune system recognizes a fake antigen as a true
antigen.
Consequently, drugs or drug metabolites causing anaphylaxis (e.g.
beta-lactams, chinolones, chlorhexidine,metamizole, muscle relaxants,
PPI, RCM, SMX/SMX-NO, etc.) are characterized by two features:
- ability to bind covalently to proteins and to form an antigen, which
is needed to induce IgE;
- ablility to form a sufficiently affine non-covalent complex
(fake antigen ), which reacts with and cross-links the preformed
IgE.
In up to 50% of patients with drug induced anaphylaxis, a prior
exposure to the drug is not documented (“anaphylaxis at first sight”)
(2, 11): Some reactions might be IgE independent (12). But if IgE was
involved, the IgE might have been induced by a different compound, which
happen to (cross-)react with the newly formed fake antigen. Under these
special conditions even a drug, which is per se not able to form
an antigen and to induce IgE, may cause anaphylaxis.
The following conditions may additionally favor anaphylaxis by fake
antigens (FAR): providing a high amount of drug; this may compensate for
moderate affinity (Ka); And administration of the drug by bolus
injection. The short-lasting, high drug concentration may generate a
tsunami of fake antigen; Example for highly-dosed and fast delived drugs
causing anaphylaxis (often at first sight) may be RCM or NMBA (2, 12);
Since fake antigens can bind and cross-link IgE/FcεRI, they could also
be used for desensitization to induce MC-unresponsiveness: However, they
need to be applied very cautiously, in small, stepwise increasing
concentrations to avoid anaphylaxis related side effects. It is
uncertain, whether the duration of induced MC-unresponsiveness caused by
fake or true antigen differs.
In this context, one should re-consider the meaning of DHR-diagnosis by
immediate skin tests (prick, i.d.) as well as by the in-vitro basophil
activation tests (BAT) (table 3) using the drug alone: Both tests rely
on drug-specific IgE and FcεRI cross-linking and are evaluated within 15
min. Although both tests need to be interpreted with caution, as they
may be false positive for various reasons, these tests detect in
principle the ability of the drug to form a fake antigen. They donot detect reactivity to the hapten-protein adduct. In contrast,
a serological assay like “ImmunoCAP” just detects drug-specific IgE
but does not give indications on the ability to elicit a FAR.
The occurrence of atopic allergies like pollinosis, allergic asthma,
etc. is not associated with drug allergy (29). Only the clinical
manifestation of drug allergy symptoms might be aggravated in acute drug
allergy, e.g. if anaphylaxis involves the lung in a patient with
allergic asthma. One might conclude that the regulation of
MC-unresponsiveness is not impaired in patients with drug allergy and
that the clinical problems of immediate drug allergy are mainly due to
the sudden formation of fake antigen.